Traditional Chinese Medicine (TCM) may provide some novel approaches to Parkinson's Disease treatment that deserve further attention by Western medicine. A prime example is electroacupuncture, a well-known type of TCM that has been used as an alternative therapy in patients with PD with some success. We propose to establish a collaboration among three institutions, Case Western Reserve University (CWRU), the University of Pittsburgh (Pitt), and China Medical University (CMU), to initiate a research program on acupuncture as an intervention for PD. General hypothesis: EA reduces the vulnerability of DA neurons to both environmental and genetic factors by activating gene expression for neurotrophic factors (NTFs) including GDNF, which then reduces the susceptibility of these neurons to ER stress and mitochondrial dysfunction. This R21 has three specific aims. Aim 1: To establish in our U.S. labs a well-characterized model of EA neuroprotection in MPTP-treated mice. In the first experiment we will use C57/b16 mice and a progressive MPTP model. Six groups will be involved: (1) acute MPTP plus 100 Hz EA, (2) MPTP plus 0 Hz acupuncture, (3) MPTP plus EA at a non-effective site, (4) MPTP treatment alone, (5) vehicle-treated mice given EA, and (6) vehicle treated mice plus sham acupuncture. Behavioral, histological and biochemical analysis will be used to assess neuroprotection after 2.5 and 5.5 weeks. Aim 2: To determine the influence of EA on indices of ER stress and mitochondrial function. Using tissue generated in Experiments 1 and 2, we will assess activation of downstream targets of ER stress, protein upregulation of UPR target genes and mitochondrial parameters using biochemical and immunohistochemical methods. Aim 3: To determine if there is an interaction between GDNF availability on the response to EA. Two different groups of GDNF null mutants will be treated acutely with MPTP, subjected to EA or sham treatments, and then EA-induced neuroprotection assessed.